Abstract The extent, nature and pathogenesis of neuro-cognitive impairments among individuals with type 1 diabetes (T1DM) are poorly understood. Patients with T1DM are living longer and thus are commonly entering an age (50+) when such impairments become more evident, but are, as yet, understudied. Past, small studies suggest aspects of cognition, brain structure, function and chemistry that may be affected by T1DM and may increase in severity and clinical importance with aging. The Diabetes Control & Complications Trial/Epidemiology of Diabetes Interventions & Complications (DCCT/EDIC) study affords an unparalleled opportunity to use longitudinal data gathered over 30 years from early in the course of illness, among this well- characterized cohort, to examine important and unresolved questions about the frequency and pathogenesis of neuro-cognitive impairments as patients enter the age of highest risk. DCCT/EDIC participants have had continuously high rates of participation (currently 94% of the surviving cohort), and are now returning for an additional five years of follow-up (2017-2022) for ongoing and new biomedical assessments including evaluation of cognitive functioning and depression. This application, submitted in response to RFA-DK-16-007, will leverage available data collected in this cohort from past evaluations and from the new planned 5-year follow-up. We plan to assess effects of risk factors including: exposure to hyperglycemia as documented by HbA1c measurements during DCCT/EDIC, recurrent severe hypoglycemic events, variation in glycemia using continuous glucose monitoring (CGM ), history of hypertension, hyperlipidemia, and presence of micro- vascular and macro-vascular complications on the integrity of the brain evaluated by magnetic resonance imaging (MRI), and the association of brain changes with neuro-retinal degeneration assessed by a novel method-Ocular Coherence Tomography (OCT). We hypothesize that the presence of T1DM, prior conventional DCCT treatment assignment, elevated HbA1c levels and history of severe hypoglycemia will lead to reduced total brain volume, our primary outcome, and also result in detectable vascular, neuro-degenerative, neuro- chemical and functional changes assessed by MRI. In addition, we postulate that these primary risk factors in concert with other secondary risk factors (e.g.: glycemic variation, hypertension & micro-vascular and macro- vascular disease), will differentially affect frontal & temporal regions. Changes in the brain will be associated with decreased cognitive functioning, especially on measures of psychomotor efficiency. To reach these goals 400 T1DM subjects from the DCCT/EDIC cohort randomly selected to represent a broad range of biomedical outcomes will be compared with a non-diabetic control population (n=100) of similar age and social/educational background using identical cognitive and neuro-imaging techniques. Completion of these aims will determine key predictors of neuro-cognitive impairments in patients with T1DM and guide personalized strategies to mitigate this risk in providing clinical care for patients with T1DM.